Methods for inhibiting preterm labor and uterine contractility disorders and preventing cervical ripening

Abstract

The invention relates to methods and pharmaceutical compositions for inhibiting or preventing preterm birth, inhibiting or delaying cervical ripening, inhibiting myometrial contractility and treating or inhibiting uterine contractility disorders. The methods comprise administering an effective amount of a composition comprising steroid hormones such as soluble progesterone.

1 . A method for inhibiting preterm birth in a subject in need thereof comprising:
 (i) providing a composition comprising a steroid hormone or a pharmaceutical equivalent, analog, derivative or a salt thereof, which inhibits preterm birth; and   (ii) administering a therapeutically effective amount of the composition to the subject to inhibit preterm birth, thereby inhibiting preterm birth.   
     
     
         2 . A method for preventing preterm birth in a subject in need thereof by the method of  claim 1 . 
     
     
         3 . A method for delaying cervical ripening in a subject in need thereof comprising:
 (i) providing a composition comprising a steroid hormone or a pharmaceutical equivalent, analog, derivative or a salt thereof, which delays cervical ripening; and   (ii) administering a therapeutically effective amount of the composition to the subject to inhibit cervical ripening, thereby inhibiting cervical ripening.   
     
     
         4 . A method for inhibiting cervical ripening in a subject in need thereof by the method of  claim 3 . 
     
     
         5 . The method of  claim 1 , wherein the composition further comprises an effective amount of an agent to render the steroid hormone soluble. 
     
     
         6 . The method of  claim 5 , wherein the agent is any one or more of cyclodextrins, sesame oil, fish oil, corn oil, olive oil, coconut oil, krill oil, omega fatty acids, mineral oil, peppermint oil, flaxseed oil, vitamin E oil, argan oil saline solution and/or glucose solution. 
     
     
         7 . The method of  claim 6 , wherein the agent is fish oil, peppermint oil or saline solution. 
     
     
         8 . The method of  claim 5 , wherein the effective amount of the agent is about 0.05-0.1 ml/mg of steroid hormone, 0.1-0.2 ml/mg of steroid hormone, 0.2-0.3 ml/mg of steroid hormone, 0.3-0.4 ml/mg of steroid hormone, 0.4-0.5 ml/mg of steroid hormone, 0.5-0.6 ml/mg of steroid hormone, 0.6-0.7 ml/mg of steroid hormone, 0.7-0.8 ml/mg of steroid hormone, 0.8-0.9 ml/mg of steroid hormone, 0.9-1.0 ml/mg of steroid hormone, 1.0-5.0 ml/mg of steroid hormone, 5.0-10.0 ml/mg of steroid hormone, 10.0-15.0 ml/mg of steroid hormone, 15.0-20.0 ml/mg of steroid hormone, 20.0-25.0 ml/mg of steroid hormone or 25.0-30.0 ml/mg of steroid hormone. 
     
     
         9 . The method of  claim 1 , wherein the composition is administered beginning at about 18 th  to about 22 nd  of gestation and ending at about 37 th  week of gestation. 
     
     
         10 . The method of  claim 1 , wherein the composition is administered beginning at about 16 th  of gestation and ending at about 37 th  week of gestation. 
     
     
         11 . The method of  claim 1 , wherein the composition is administered beginning at the time of positive pregnancy until the 37 th  week of gestation or from time preterm labor is suspected to a time when delivery is imminent. 
     
     
         12 . The method of  claim 1 , wherein the composition is administered for about 2 to 4 weeks, for about 4 to 6 weeks, for about 6 to 8 weeks, for about 8 to 10 weeks, for about 10 to 12 weeks, for about 12 to 14 weeks or for about 14 to 19 weeks. 
     
     
         13 . The method of  claim 1 , wherein the composition is administered for about 20 weeks, for about 21 weeks, for about 22 weeks, for about 23 weeks, for about 25 weeks, for about 26 weeks, for about 27 weeks, for about 28 weeks or for about 29 weeks. 
     
     
         14 . The method of  claim 1 , wherein the steroid hormone is a progestogen or a pharmaceutical equivalent, analog, derivative or a salt thereof. 
     
     
         15 . The method of  claim 14 , wherein the progestogen is a compound having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutical equivalent, analog, derivative or a salt thereof. 
       
     
     
         16 . The method of  claim 14 , wherein the progestogen is progesterone (P4) or a pharmaceutical equivalent, analog, derivative or a salt thereof. 
     
     
         17 . The method of  claim 14 , wherein the progestogen is 17-hydroxyprogesterone (17OHP) or a pharmaceutical equivalent, analog, derivative or a salt thereof. 
     
     
         18 . The method of  claim 14 , wherein the progestogen is a progestin. 
     
     
         19 . The method of  claim 18 , wherein the progestin is 17-hydroxyprogesterone caproate (17P) or promegestone (R5020). 
     
     
         20 . The method of  claim 1 , wherein the composition is in a soluble form, crystalline form, gel form, tablet form or encapsulated form. 
     
     
         21 . The method of  claim 1 , wherein the composition is administered subcutaneously, intradermally, intravenously, intramuscularly, intraperitonealy, orally, vaginally or via inhalation. 
     
     
         22 . The method of  claim 1 , wherein the composition is administered topically. 
     
     
         23 . The method of  claim 1 , wherein the effective amount of the steroid hormone is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day, 95-100 mg/day, 100-200 mg/day, 200-300 mg/day, 300-500 mg/day, 500-700 mg/day, 700-1000 mg/day, 1000-2000 mg/day, 2000-3000 mg/day, 3000-4000 mg/day or 4000-5000 mg/day. 
     
     
         24 . A method for inhibiting myometrial contractility in a subject in need thereof comprising:
 (i) providing a composition comprising progesterone (P4) or a pharmaceutical equivalent, analog, derivative or a salt thereof, which inhibit myometrial contractility; and   (ii) administering a therapeutically effective amount of the composition to the subject to inhibit myometrial contractility, thereby inhibiting myometrial contractility.   
     
     
         25 . A method for treating uterine contractility disorders in a subject in need thereof by the method of  claim 24 . 
     
     
         26 . A method for inhibiting uterine contractility disorders in a subject in need thereof by the method of  claim 24 . 
     
     
         27 . The method of  claim 24 , wherein the composition further comprises an agent to render the steroid hormone soluble. 
     
     
         28 . The method of  claim 27 , wherein the agent is any one or more of cyclodextrins, sesame oil, fish oil, corn oil, olive oil, coconut oil, krill oil, omega fatty acids, mineral oil, peppermint oil, flaxseed oil, vitamin E oil, argan oil, saline solution and/or glucose solution. 
     
     
         29 . The method of  claim 24 , wherein the composition further comprises an effective amount of nifedipine or indomethacin. 
     
     
         30 . The method of  claim 24 , wherein the composition is administered subcutaneously, intradermally, intravenously, intramuscularly, intraperitonealy, orally, vaginally or via inhalation. 
     
     
         31 . The method of  claim 24 , wherein the composition is administered topically. 
     
     
         32 . The method of  claim 1 , wherein the subject is selected from the group consisting of human, non-human primate, monkey, ape, dog, cat, cow, horse, rabbit, mouse, pig and rat. 
     
     
         33 . The method of  claim 27 , wherein the subject is human. 
     
     
         34 . The method of  claim 24 , wherein the effective amount of composition is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day 95-100 mg/day, 100-200 mg/day, 200-300 mg/day, 300-500 mg/day, 500-700 mg/day, 700-1000 mg/day, 1000-2000 mg/day, 2000-3000 mg/day, 3000-4000 mg/day or 4000-5000 mg/day. 
     
     
         35 . The method of  claim 29 , wherein progesterone and nifedipine are administered concurrently or sequentially. 
     
     
         36 . The method of  claim 29 , wherein progesterone and indomethacin are administered concurrently or sequentially. 
     
     
         37 . The method of  claim 29 , wherein the effective amount of nifedipine is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day or 95-100 mg/day. 
     
     
         38 . The method of  claim 29 , wherein the effective amount of indomethacin is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day or 95-100 mg/day. 
     
     
         39 . The method of  claim 6 , wherein cyclodextrins are selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin. 
     
     
         40 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutical equivalent, derivative, analog, and/or salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         41 . The pharmaceutical composition of  claim 40 , further comprising an agent to render the compound soluble. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the agent is any one or more of cyclodextrins, sesame oil, fish oil, corn oil, olive oil, coconut oil, krill oil, omega fatty acids, mineral oil, peppermint oil, flaxseed oil, vitamin E oil, argan oil, saline solution and/or glucose solution. 
     
     
         43 . The pharmaceutical composition of  claim 40 , further comprising an effective amount of nifedipine and/or indomethacin. 
     
     
         44 . The pharmaceutical composition of  claim 41 , wherein an effective amount of the agent is about 0.05-0.1 ml/mg of steroid hormone, 0.1-0.2 ml/mg of steroid hormone, 0.2-0.3 ml/mg of steroid hormone, 0.3-0.4 ml/mg of steroid hormone, 0.4-0.5 ml/mg of steroid hormone, 0.5-0.6 ml/mg of steroid hormone, 0.6-0.7 ml/mg of steroid hormone, 0.7-0.8 ml/mg of steroid hormone, 0.8-0.9 ml/mg of steroid hormone, 0.9-1.0 ml/mg of steroid hormone, 1.0-5.0 ml/mg of steroid hormone, 5.0-10.0 ml/mg of steroid hormone, 10.0-15.0 ml/mg of steroid hormone, 15.0-20.0 ml/mg of steroid hormone, 20.0-25.0 ml/mg of steroid hormone or 25.0-30.0 ml/mg of steroid hormone. 
     
     
         45 . The pharmaceutical composition of  claim 43 , wherein the effective amount of indomethacin is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day or 95-100 mg/day. 
     
     
         46 . The pharmaceutical composition of  claim 43 , wherein the effective amount of nifedipine is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day or 95-100 mg/day. 
     
     
         47 . The pharmaceutical composition of  claim 40 , wherein the therapeutically effective amount of the steroid hormone is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95 mg/day, 95-100 mg/day, 100-200 mg/day, 200-300 mg/day, 300-500 mg/day, 500-700 mg/day, 700-1000 mg/day, 1000-2000 mg/day, 2000-3000 mg/day, 3000-4000 mg/day or 4000-5000 mg/day. 
     
     
         48 . The pharmaceutical composition of  claim 42 , wherein the agent is fish oil, peppermint oil or saline solution. 
     
     
         49 . A method of increasing bioavailability of a steroid hormone comprising:
 (i) providing a composition comprising a steroid hormone or a pharmaceutical equivalent, analog, derivative or a salt thereof; and   (ii) administering a therapeutically effective amount of the composition via topical delivery, thereby increasing bioavailability of the steroid hormone.   
     
     
         50 . The method of  claim 49 , wherein the therapeutically effective composition comprises an effective amount of an agent to render the steroid hormone soluble, the steroid hormone or a pharmaceutical equivalent, analog, derivative or a salt thereof comprises a progestogen, and increasing bioavailability comprises higher levels of the progestogen in blood plasma.